1. Field of the Invention
This invention relates generally to compositions and methods involved in the therapeutic use of protein C. Specifically, the invention is directed to a novel protein C that is activated by free thrombin at an increased rate, and upon activation, exhibits the protective anti-inflammatory and anti-apoptotic properties of wild-type activated protein C, but lacks the anti-coagulant properties responsible for excessive bleeding in some individuals. This novel protein C and its activated derivative may be useful for treating diseases which involve inflammation or apoptosis, such as severe sepsis.
2. Description of the Related Art
Activated protein C (APC), exhibits anti-inflammatory, cytoprotective, and potent anti-coagulant activity properties. In addition, recombinant activated protein C (APC) has been approved as a drug for treating severe sepsis, and has reduced mortality in these patients (See Bernard et al. (2001) N Eng J Med.; 344:699-709). Studies have also shown that APC may protect the endothelial cells of the brain from damage caused by ischemic stroke (Cheng et al. (2003) Nature Med.; 9:338-342).
There is growing evidence that the protective effects associated with APC when administered therapeutically are separate from its anti-coagulant effect, and that these protective effects are attributed to cell signaling by APC in the endothelium (Taylor et al. (1987) J Clin Invest. 1987; 79:918-925; Feistritzer et al. (2005) Blood; 105:3178-3184; Mosnier et al. (2003) Biochem J.; 373:65-70; Cheng et al. (2003) Nature Med.; 9:338-342; Guo et al. (2004) 41:563-572). An increased incidence of bleeding remains a major drawback of APC treatment (Bernard et al. (2001) N Eng J Med.; 344:699-709). This risk of bleeding prevents medical practitioners from fully utilizing APC therapy. Practitioners also require more treatment options, for example, a zymogen form of protein C that is more efficiently activated, particularly under inflammatory conditions. To our knowledge, these problems have not been solved. Protein C is activated inefficiently independent of the thrombin TM complex, and APC continues to include a high risk of bleeding. Therefore, there is a need for a protein C that is readily activated by free thrombin, and an APC with diminished anti-coagulant activity and normal cytoprotective properties.